Posted on 10/10/2012 7:49:50 PM PDT by neverdem
According to George Bernard Shaw: "The most intolerable pain is produced by prolonging the keenest pleasure." Not to be picky George, but actually both sensations result from the activity of a diverse family of proteins on the surface of cells. This year's Nobel Prize in chemistry was awarded to two Americans—Robert Lefkowitz of Duke University in Durham, North Carolina, and Brian Kobilka of Stanford University School of Medicine in Palo Alto, California—who revealed the inner workings of these proteins, which also orchestrate a variety of things such as the way we see, smell, taste, feel, and fight infections.
The notion that a single family of proteins was responsible for so many different physiological processes was far from evident early on. One hint came at the end of the 19th century, when scientists studying the effects of the hormone adrenaline discovered that it had different effects in various parts of the body. It made heart rate and blood pressure increase, but it decreased digestive activity and caused pupils to relax. One idea was that proteins called receptors on different cells somehow captured adrenaline molecules and either ferried the hormone into cells or transferred a message inside to trigger a response. In the 1940s, an American biologist named Raymond Ahlquist made enough progress to conclude that there must be two types of adrenaline receptors, one that caused smooth muscle cells to contract, and the other that stimulated the heart.
Lefkowitz picked up the trail in the early 1960s. Then a young cardiology student at the National Institutes of Health in Bethesda, Maryland, Lefkowitz was working with adrenocorticotropic hormone, which stimulates the production of adrenaline in the adrenal gland. He modified the hormone, tagging it with radioactive iodine, and then tracked its binding to adrenal membrane material. He and others later used the same strategy to track adrenaline itself, and eventually map out nine different subtypes of adrenergic receptors, known as α ARs and β ARs.
In the 1980s, Lefkowitz set out to identify the gene for the β AR receptors. After a student purified bits of the receptor and teased out a few fragments of its gene, Kobilka, who had joined Lefkowitz's lab, used them to fish out the full gene. The group quickly noticed that the gene showed marked similarities to one for rhodopsin, the light receptor in the retina of the eye. Both had seven rodlike regions that snaked through the cell membrane and coupled to so-called G-proteins inside the cells. By this time, other groups had discovered some 30 other receptors that work with G-proteins, which transmit signals into cells and were the subject of the 1994 Nobel Prize in physiology or medicine. And in what he later described as a "real Eureka moment," Lefkowitz, along with Kobilka and the rest of the group, concluded that there was likely an entire family of receptors that look alike and function in the same manner. Today, some 800 GPCRs, also known as seven-transmembrane receptors, have been identified.
After completing his work at Duke, Kobilka took an appointment at Stanford University and set about to capture a three-dimensional picture of the β AR receptor. Using the receptor's gene, the group produced millions of copies of individual GPCRs and coaxed them into crystallizing into a solid. They determined that the atomic structure of the protein by firing a tight beam of x-rays at the crystal and charting exactly how the atoms in the crystal caused the x-rays to ricochet off.
But the size and flexibility of GPCRs was a problem for traditional x-ray crystallography. Kobilka's team needed ways to stabilize the floppy receptor, primarily the portion of the proteins that protruded outside the cells, as well as the G-protein binding site on the inside. Progress was painfully slow. Kobilka even lost his funding from the Howard Hughes Medical Institute when results sputtered. But by 2007, Kobilka and his colleagues had come up with enough tricks for stabilizing the molecule that they were able to come up with the first crystal structure of the inactive GPCR. And in what other experts call a tour de force, in 2011 the group reported in Nature that it had obtained a high-resolution structure of the GPCR not only with the external domain being activated by a receptor stimulator, but with the internal region bound to a G-protein. The structures revealed in full atomic glory that when a hormone or another trigger molecule binds to the receptor, this causes the external portions of the seven-transmembrane rods to pinch together, which forces the opposite ends of those rods apart. This creates a cleft in the portion of the protein inside the cell, allowing a G-protein to bind, which in turn triggers a series of a cascade of intracellular reactions. "These proteins evolved to be very efficient at detecting small things on the outside of cells and making a big change on the inside of a cell," Kobilka says. "Once that challenge was overcome in evolution, it was used over and over again," he adds.
That has made GPCRs not only one of the most versatile families of proteins, but also one of the most medically important. Today, compounds that target GPCRs make up 30% to 50% of all drugs on the market, and continue to make up one of the hottest areas of research in medicine. "There have been a lot of people that have contributed to the advances in this field," says Charles "Chuck" Sanders, a structural biologist at Vanderbilt University in Nashville. "But these two stand out. This is an extremely well deserved award for them."
Sort of like an erection lasting over four hours after taking Cialas?
Well done.
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